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Inhibition of human glutathione reductase by the nitrosourea drugs 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea. A crystallographic analysis.

Karplus PA, Krauth-Siegel RL, Schirmer RH, Schulz GE
Eur J Biochem 171 193-8 (1988)
Cited: 40 times
EuropePMC logo PMID: 3338461

Abstract

Glutathione reductase from human erythrocytes was inhibited by incubation with the drugs 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (HeCNU) under quasi-physiological conditions. For reference purposes, iodoacetamide was used for inactivating alkylation of the enzyme. In each case the modified glutathione reductase was crystallized and its structure determined. These analyses showed that in all experiments the enzyme had reacted at the distal sulfur, that is at the thiol of Cys-58, and virtually nowhere else in the visible structure. The electron density of the HeCNU derivative at 0.3 nm resolution is consistent with a 2-hydroxyethyl group. This alkyl moiety has recently been identified by chemical analysis [Schirmer, R. H., Schöllhammer, T., Eisenbrand, G. and Krauth-Siegel, R. L. (1987) Free Radical Res. Commun. 3, 3-12]. The 0.2 nm resolution electron-density map of the BCNU-derivatized enzyme cannot be explained by a 2-hydroxyethyl group. Instead the modification appears as a carbamoyl moiety containing at least five non-hydrogen atoms. In this derivative the distal cysteine is forced into an unusual conformation.

Reviews - 1grh mentioned but not cited (1)

  1. Thioredoxin reductase and its inhibitors. Saccoccia F, Angelucci F, Boumis G, Carotti D, Desiato G, Miele AE, Bellelli A. Curr Protein Pept Sci 15 621-646 (2014)


Reviews citing this publication (6)

  1. Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. Becker K, Tilley L, Vennerstrom JL, Roberts D, Rogerson S, Ginsburg H. Int. J. Parasitol. 34 163-189 (2004)
  2. The thioredoxin system--from science to clinic. Gromer S, Urig S, Becker K. Med Res Rev 24 40-89 (2004)
  3. Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia. Krauth-Siegel RL, Bauer H, Schirmer RH. Angew. Chem. Int. Ed. Engl. 44 690-715 (2005)
  4. Drug bioactivation, covalent binding to target proteins and toxicity relevance. Zhou S, Chan E, Duan W, Huang M, Chen YZ. Drug Metab. Rev. 37 41-213 (2005)
  5. Glutathione--functions and metabolism in the malarial parasite Plasmodium falciparum. Becker K, Rahlfs S, Nickel C, Schirmer RH. Biol. Chem. 384 551-566 (2003)
  6. Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment. Noble M, Mayer-Pröschel M, Li Z, Dong T, Cui W, Pröschel C, Ambeskovic I, Dietrich J, Han R, Yang YM, Folts C, Stripay J, Chen HY, Stevens BM. Free Radic. Biol. Med. 79 300-323 (2015)

Articles citing this publication (33)

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